BACKGROUND: The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood and exerts anti-inflammatory and neuroprotective effects. Its projections reach hypothalamic nuclei which regulate the neuroendocrine stress response. Changes in noradrenergic signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. Associated studies of our study group—investigating stress response in obese and non-obese subjects—have shown increased activity of the stress axes including an association between hypothalamic-pituitary-adrenal (HPA) axis responsiveness and central noradrenaline transporter.
OBJECTIVES: (i) To evaluate central NA transporter (NAT) availability in vivo in
immunotherapy-naïve relapsing-remitting multiple sclerosis (RRMS) patients compared to healthy controls (HC), (ii) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and the arginine-vasopressin surrogate (AVP) copeptin in patients with RRMS and clinically isolated syndrome (CIS) compared to HC, (iii) to test whether HPA axis responsiveness is differentially associated to NAT availability in RRMS patients and HC.
METHODS: 22 patients (11 RRMS, 11 CIS) were enrolled and compared to 22 sex- and age-matched HC. (i) Positron emission tomography (PET) was performed in 11 RRMS and 12 HC applying the NAT-selective radiotracer S,S-[11C]O-methylreboxetine ([11C]MRB) for intergroup comparison. (ii) All patients underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters, and copeptin after dexamethasone intake were derived. (iii) MRB-PET imaging data were correlated to curve indicators and copeptin obtained from the dex/CRH test in RRMS patients.
RESULTS: (i) RRMS patients show increased NAT availability in almost all subcortical regions, reaching statistical significance in the thalamus, amygdala, putamen and pons/midbrain. No association with clinical or psychometric variables was found. (ii) Immunotherapy-naïve RRMS patients show no significant changes in cortisol, ACTH or copeptin indices. (iii) There is no correlation between HPA axis indicators and NAT availability in RRMS patients. In HC, NAT availability correlated positively with cortisol curve indicators.
CONCLUSION: This study supports the evidence for increased NAT availability in
immunotherapy-naïve RRMS patients compared to HC. The increased NAT availability was shown in the subcortical brain regions (relevant to attention and emotional regulation) of the RRMS patients. In this cohort, no correlation with physical or psychometric scores was found. It will be further of interest, if these NAT changes longitudinally predispose to the psychiatric comorbidities which are frequently seen in MS patients or if they do in larger, more heterogenous sample sizes. Our cohort of early RRMS and CIS did not display a statistically significant alteration in the HPA axis responsiveness compared to HC. No association between
NAT availability and HPA axis responsiveness could be detected in RRMS patients.:TABLE OF CONTENTS
LIST OF ABBREVIATIONS…………………….………………………………………......4
LIST OF FIGURES…..….………………………….….……..…………………………..…5
I BIBLIOGRAPHIC DESCRIPTION…………………………..……………………………6
II INTRODUCTION…..…..………………………………………………………….............7
2.1 Multiple sclerosis — Background and scope……………....…………………..........7
2.1.1 Diagnostic criteria, subtypes and clinical features……….............….…………....7
2.1.2 Multiple sclerosis and its impact on daily life: fatigue.…...…...….............………9
2.2. Noradrenaline — neurotransmitter and immunomodulator…...…………….........10
2.2.1 Noradrenaline in the context of multiple sclerosis…………………….................11
2.2.2 Noradrenaline in the context of neuroinflammation and neurogenesis.............12
2.3 Noradrenaline transporter as regulator of noradrenergic transmission….…........13
2.3.1 Noradrenaline transporter imaging……………………………............................14
2.4 Neuroendocrine stress response……...…..……………………..……..……….......14
2.4.1 Noradrenaline in the context of stress response regulation…...........................15
2.4.2 Stress axis regulation in multiple sclerosis……….............……….....................16
III METHODS……………......……………………………………………………..……....19
3.1 Objectives and hypotheses.....……..…………………………………………….......19
3.2 Study design………………..….....………………………………….…..…………….20
3.3 Hypothalamic-pituitary-adrenal axis assessment using the combined
dexamethasone/CRH test…….……...........……….....................................................21
3.4 Questionnaires……...…………………….....…………………………………………22
3.4.1 Beck-Depression-Inventory……………….............……….………………………22
3.4.2 Würzburger Erschöpfungsinventar bei MS….…………..….............……………22
3.5 PET imaging, imaging data processing and analysis………………….....………..23
3.6 Statistical analysis………………….………………………………………….....……23
IV RESULTS………….......……………………………………………….........................24
4.1 Changes of central noradrenaline transporter availability in
immunotherapy-naïve multiple sclerosis patients – Publication….....……...…………24
4.2 HPA axis responsiveness does not differ between HC and RRMS
or CIS patients…...………………………………...……………………………………….25
4.3 In RRMS patients, noradrenaline transporter availability of selected brain
regions does not correlate with neuroendocrine indicators of stress
responsiveness, but do positively correlate in healthy controls………………..….…..25
V SUMMARY………………….…………………………………………………………….31
5.1 Significantly changed noradrenaline transporter availability in RRMS
patients in brain regions relevant to attention, vigilance and mood………….............31
5.2 Noradrenaline transporter availability is not significantly associated with
psychometric and physical scores……..…………………...........................................32
5.3 HPA responsiveness does not significantly differ between early-stage
RRMS patients, CIS patients and healthy controls………..…………………..............32
5.4 NAT DVR of selected brain regions do not reveal a significant association
to HPA response in RRMS patients, but in healthy controls………...……..................33
5.5 Limitations..………………………………………………………………………….....35
5.6 Future directions…………………………………………………………………….....35
VI PUBLICATION BIBLIOGRAPHY…….……………………....…………….................36
VII ANHANG…….………..…...…..………..………………………………………………49
7.1 Publikationen…………..……….....…..……………………………………................49
7.1.1 Publikationen als Ko-Autorin…...…………..………..............…………………….50
7.1.1.1 Central noradrenaline transporter availability is linked with HPA
axis responsiveness and copeptin in human obesity and non-obese controls……..50
7.1.1.2 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity...............................................................................51
7.2 Erklärung zum wissenschaftlichen Beitrag der Promovendin
zur Publikationspromotion…………...........………………………………………………52
7.3 Erklärung über die eigenständige Abfassung der Arbeit...…....…………...…......53
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:79096 |
| Date | 09 May 2022 |
| Creators | Preller, Elisa Ruth |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English, German |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | https://doi.org/10.1038/s41598-020-70732-5 |
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